[AT(1) and AT(2) angiotensin II receptors: key features]

Abstract

The angiotensin AT(1) and AT(2) receptors have been cloned and characterised. Both are members of the serpentine receptor superfamily coupled to G proteins, but there is only 32% homology between the AT(1) and AT(2) receptors. The typical pharmacological features of AT(1) receptors are their selective affinity for biphenylimidazoles (typified by losartan) and their insensitivity to tetrahydroimidazopyridine (such as PD123319). In contrast, the AT(2) receptor has the opposite sensitivity for these two ligands. Genes located on chromosome 3 and X, respectively, encode the human AT(1) and AT(2) receptors. The signalling pathways of AT(1) and AT(2) are totally different. In addition to the classical signal transduction mechanisms (phospholipases C, D, A, voltage-dependent calcium channels and adenylate cyclase), the AT(1) receptor stimulates the phosphorylation of several tyrosine-containing proteins such as Jak 2, Stat 1 and mitogen-activated protein kinases. It also activates the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. The AT(1) receptor is responsible for the majority of the effects of angiotensin II: vasoconstriction, sodium re-absorption, cell proliferation, extracellular matrix formation, inflammatory response and oxidative stress. The AT(2) receptor is expressed abundantly in fetal tissues but at low density in adults. It is, however, upregulated in various pathological circumstances such as heart failure. In contrast to the AT(1) receptor, the signalling pathway of the AT(2) receptor does not induce an increase in inositol triphosphate and diacylglycerate formation with calcium mobilisation. Activation of the AT(2) receptor stimulates an intracellular mechanism involving various Tyr (tyrosine) and Ser (serine)/Thr (threonine) phosphatases, nitric oxide/cyclic guanosine monophosphate (cGMP) and phospholipase A(2). The effect of the AT(2) receptor counterbalances that of the AT(1) receptor: inactivation of mitogen-activated protein kinase (MAP), antiproliferation, promotion of apoptosis, opening of delayed-rectifier K(+) channels, closing of T-type Ca(2+) channels, stimulation of nerve differentiation and regeneration. It has been hypothesised that stimulation of the AT(2) receptor is part of the mechanism of action of the AT(1) receptor antagonists.